Process for the production of crystals of a benzoic acid derivative

ABSTRACT

A method for preparing a crystal of 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid having a single endothermic peak approximately at 233° C. in differential scanning calorimetry, which comprises the step of recrystallizing a crystal of 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid from a mixture of water and ethanol. The method enables selective preparation of type-II crystals which are stable against physical impact. The resulting crystals are free from highly toxic hexane as a residual solvent, and preferably used as an active ingredient of pharmaceuticals.

TECHNICAL FIELD

[0001] The present invention relates to a method for selectivepreparation of a particular crystal of4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid useful as an active ingredient of a medicament.

BACKGROUND ART

[0002]4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid has retinoid activity, and its use as an active ingredient of amedicament has been expected. Conventionally, this compound is known toexist at least as two kinds of crystal polymorphs, that is, (1) acrystal melting at 193° C. and (2) a crystal melting at 233° C. [see,Japanese Patent No. 3001632 as for (1), and Japanese Patent UnexaminedPublication (Kokai) No. 61-76440 as for (2). (3) A crystal melting at205.5° C. to 206.5° C. is disclosed in Chem. Pharm. Bull., 32, p.4209,1984. However, this crystal was later reported to actually have themelting point of 231° C. to 232° C. and thus revealed to be identical tothe crystal (2) (J. Cellular Physiology, 135, pp.179-188, 1988)].

[0003] The crystal described in Japanese Patent No. 3001632, which meltsat 193° C., is prepared by using a mixture of methanol and water as arecrystallization solvent. The crystal that melts at 233° C. is preparedby using a mixture of ethyl acetate and hexane as a recrystallizationsolvent. The latter crystal (melting point: 233° C.) contains 1200 ppmand 190 ppm of residual ethyl acetate and hexane, respectively, and thushas a problem that the crystal can hardly satisfy the standard values ofresidual solvents provided by the Ministry of Health and Welfare (ethylacetate: 5000 ppm or less; hexane: 290 ppm). Whilst, the crystal thatmelts at 193° C. has a characteristic feature that a residual methanollevel can be significantly lowered.

[0004] However, the crystal that melts at 193° C. has a problem that thecrystalline form readily occurs transition by physical impact, and thuspreparation thereof as a uniform crystal is extremely difficult.Accordingly, this crystal lacks an aptitude as a raw material for largescale manufacture of a pharmaceutical product that constantly meetsquality standard. Whilst the crystal that melts at 233° C. has beenrevealed to have high stability against physical impact, as well asagainst heat, temperature, light and the like. However, a method forselective preparation of this crystal has not been known so far.Further, a method is known for preparation of the crystal that melts at233° C. in which a mixture of ethyl acetate and hexane are used as arecrystallization solvent. However, hexane is classified as Class 2solvent according to the guidelines for residual solvents ofpharmaceutical products, and is undesirable solvent to be remained inpharmaceutical preparations. Accordingly, a crystal is strongly desiredthat does not contain hexane as a residual solvent.

DISCLOSURE OF THE INVENTION

[0005] An object of the present invention is to provide a method forselective preparation of the crystal that melts at 233° C. amongcrystals of4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid, and the above crystal that does not contain hexane as residualsolvent.

[0006] The inventors of the present invention conducted various studiesto achieve the foregoing object. As a result, they found that thecrystal that melts at 233° C. can be selectively prepared byrecrystallization using a mixture of ethanol and water. Conventionally,it has been known that the crystal that melts at 193° C. can beselectively prepared by using a mixture of ethanol and water. It isindeed surprising that the crystal of different crystalline form can beselectively obtained by using the mixture of ethanol and water.

[0007] The present invention thus provides a method for preparing acrystal of4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid having a single endothermic peak approximately at 233° C. indifferential scanning calorimetry, which comprises the step ofrecrystallizing a crystal of4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid from a mixture of water and ethanol. According to a preferredembodiment, the aforementioned method wherein a volume ratio of ethanoland water is in the range of 8:5 to 1:1 is provided.

[0008] The present invention also provides a method for preparing acrystal of4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid having a single endothermic peak approximately at 233° C. indifferential scanning calorimetry, which comprises the step of heating acrystal of4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid having endothermic peaks approximately at 193° C. and 233° C. indifferential scanning calorimetry. According to a preferred embodiment,the crystal can be heated at a temperature around 200° C.

[0009] From another aspect of the present invention, there is alsoprovided a crystal of4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid having a single endothermic peak approximately at 233° C. indifferential scanning calorimetry, which is characterized not to containhexane and/or ethyl acetate as a residual solvent. The present inventionfurther provides a crystal of4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid having a single endothermic peak approximately at 233° C. indifferential scanning calorimetry, which contains 2,000 ppm or less ofresidual ethanol after the crystal is dried at 110° C. to 120° C. underreduced pressure, and a crystal of4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid having endothermic peaks approximately at 193° C. and 233° C. indifferential scanning calorimetry.

[0010] Further, the present invention provides use of a crystal of the4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid having a single endothermic peak approximately at 233° C. indifferential scanning calorimetry, which is characterized not to containhexane and/or ethyl acetate as a residual solvent, for manufacture of apharmaceutical product, and a medicament comprising the aforementionedcrystal as an active ingredient. Examples of the aforementionedmedicament include a medicament for therapeutic treatment of acutepromyelocytic leukemia, a medicament for therapeutic treatment ofpsoriasis and pustulosis palmaris et plantaris and the like.

BEST MODE FOR CARRYING OUT THE INVENTION

[0011] Types of crystals of4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid used as a raw material for the method of the present invention arenot particularly limited. Any crystals may be used in addition to thecrystal that melts at 193° C. (the aforementioned crystal (1)).According to the studies of the inventors of the present invention, thecrystal that melts at 193° C. (referred to as “type-I crystal”)described in Japanese Patent No. 3001632 gives a single endothermic peakapproximately at 194° C. in differential scanning calorimetry (DSC).Further, the crystal that melts at 233° C. (referred to as “type-Icrystal”) described in Japanese Patent Unexamined Publication No.61-76440 gives a single endothermic peak approximately at 233° C. indifferential scanning calorimetry. Besides these crystals, the inventorsof the present invention has recognized the existence of a crystal thatgives an endothermic peak approximately at 193° C. in differentialscanning calorimetry and simultaneously occurs exothermic transition togive an endothermic peak approximately at 233° C. (referred to as“type-III crystal”, see, Example 3 of the specification). In thespecification, this crystal is defined as a crystal of4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-aphthalenyl)carbamoyl]benzoicacid that has endothermic peaks approximately at 193° C. and 233° C. indifferential scanning calorimetry. Any of the aforementioned crystalsmay be used as a raw material for the method of the present invention.

[0012] Crystalline forms can be reliably identified by performing powderX-ray diffraction analysis in addition to differential scanningcalorimetry. Powder X-ray diffraction patterns of the aforementionedtype-I and type-II crystals are shown in FIGS. 5 and 6 of JapanesePatent No. 3001632 and can be easily identified by those skilled in theart. Further, the results of thermal analyses of the aforementionedtype-I and type-II crystals are shown in FIGS. 3 and 4 of theaforementioned patent document, respectively. An experimental error inmeasurement of melting point, differential scanning calorimetry and thelike is approximately a few degrees, usually within 2° C., preferablywithin 1° C., more preferably within 0.5° C.

[0013] The method of the present invention is characterized in that amixture of ethanol and water is used as a recrystallization solvent for4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid. A mixing ratio of ethanol and water at crystallization is notparticularly limited. For example, ethanol:water is preferably in therange of about 8:5 to 1:1. When the proportion of ethanol become higherthan the above range, a mixture of type-I crystals and type-II crystalsmay sometimes be obtained.

[0014] A process for recrystallization is not particularly limited, andan ordinary recrystallization process may be employed. For example, acrystal of4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid as a raw material may be completely dissolved in a mixture ofethanol and water, and then the solution may be gradually cooled andprecipitated crystals are collected by filtration. Alternatively, acrystal as a raw material may be dissolved in ethanol with heating, andthen the solution may be added with an appropriate amount of hot waterto prepare an ethanol-water mixture in a given ratio for crystallizationof the desired substance. In order to efficiently crystallize theobjective substance, a seed crystal may be added. An amount of the seedcrystal is not particularly limited. The amount may be about 1/1,000 to1/1,000,000, preferably about 1/80,000, based on the weight of thecrystal used as a raw material. The crystals collected by filtration canbe generally dried with heating at about 110° C. to 120° C. underreduced pressure to remove the recrystallization solvent.

[0015] Further, when a crystal of4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid having endothermic peaks approximately at 193° C. and 233° C. indifferential scanning calorimetry is heated to obtain a crystal of4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid having a single endothermic peak approximately at 233° C. indifferential scanning calorimetry, a heating temperature may generallybe 180° C. or higher, preferably 200° C. or higher, most preferablyabout 200° C. to 210° C.

[0016] The crystal of4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid provided by the method of the present invention is manufacturedwithout using a recrystallization solvent containing hexane, andaccordingly, the crystal is characterized not to substantially containhexane as a residual solvent. For example, after dryness with heating at110° C. to 120° C. under reduced pressure of 30 mmHg or lower for 22hours, residual ethanol contained in the crystals is usually 2,000 ppmor less, preferably 1,000 ppm or less, more preferably 500 ppm or less.Ethanol is a low toxic solvent which is classified as Class 3 solventamong residual solvents in pharmaceutical products according toprovisions by the Ministry of Health and Welfare. Accordingly, thecrystal of the present invention can be preferably used as an activeingredient of pharmaceuticals.

EXAMPLES

[0017] The present invention will be explained more specifically withreference to the following examples. However, the scope of the presentinvention is not limited to these examples.

Example 1

[0018]4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid (10.0 g) was added to a mixture of ethanol (130 mL) and water (120mL) and dissolved with heating, and then the solution was graduallycooled and the precipitated crystals were collected by filtration. Theresulting wet crystals were dried at 110° C. to 120° C. under reducedpressure to obtain crystals. The resulting crystals were subjected todifferential scanning calorimetry, and as a result, the crystals gave asingle endothermic peak approximately at 233° C. Further, the powderX-ray diffraction pattern of the crystals was identical to the powderX-ray diffraction pattern shown in FIG. 6 of Japanese Patent No.3001632, which verified that the crystals were type-II crystals.

Example 2

[0019] Crystals were obtained in the same manner as in Example 1 exceptthat the recrystallization solvent was changed to a mixture of ethanol(150 mL) and water (100 mL). The resulting crystals were subjected todifferential scanning calorimetry, and as a result, the crystals gave asingle endothermic peak approximately at 233° C. Further, the powderX-ray diffraction pattern of these crystals was identical to the powderX-ray diffraction pattern shown in FIG. 6 in Japanese Patent No.3001632, which verified that the crystals were type-II crystals.

Example 3

[0020] Crystals were obtained in the same manner as in Example 1 exceptthat the recrystallization solvent was changed to a mixture of ethanol(170 mL) and water (80 mL). The resulting crystals were subjected todifferential scanning calorimetry, and as a result, the crystals gavetwo endothermic peaks approximately at 193° C. and 233° C. Thesecrystals were termed as “type-III crystals”.

Example 4

[0021] The type-III crystals obtained in Example 3 were heated at 200°C. to 205° C. for 2 hours under reduced pressure. The resulting crystalswere subjected to differential scanning calorimetry, and as a result,the crystals gave a single endothermic peak approximately at 233° C.Further, the powder X-ray diffraction pattern of the resulting crystalswas identical to the powder X-ray diffraction pattern shown in FIG. 6 inJapanese Patent No. 3001632, which verified that the crystals weretype-II crystals.

Comparative Example 1

[0022]4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid (20.0 g) was added to a mixture of methanol (200 mL) and water (20mL) and dissolved with heating, and then cooled to room temperature. Thesolution was added dropwise slowly with water (40 mL), and theprecipitated crystals were collected by filtration and dried at 110° C.to 120° C. under reduced pressure to obtain crystals. The resultingcrystals were subjected to differential scanning calorimetry, and as aresult, the crystals gave a single endothermic peak at approximately193° C. Further, the powder X-ray diffraction pattern of these crystalswas identical to the powder X-ray diffraction pattern shown in FIG. 5 ofJapanese Patent No. 3001632, which verified that the resulting crystalswere type-I crystals.

Test Example 1

[0023] Grain size distributions of the crystals obtained in Example 1and Comparative Example 1 were measured. A laser-type grain sizeanalyzer (Microtrac FRA) was used. A 1% aqueous solution of Soprophor FL(3 ml, Rhone-Poulenc) was added with water (15 ml), and an appropriateamount of the crystals obtained in Example 1 or Comparative Example 1were dispersed in the mixture to obtain a sample dispersion. The resultsare shown in Table 1. As a result, the crystals obtained by the methodof the present invention were revealed to have a smaller fluctuation inthe average grain size, and found to be suitable for manufacture oftablets with uniform quality. TABLE 1 Average grain size Methanol/waterEthanol/water 10% (μm) 42.74 16.38 50% (μm) 96.29 39.74 90% (μm) 268.7586.92

INDUSTRIAL APPLICABILITY

[0024] According to the method of the present invention, the type-IIcrystals stable against physical impact can be selectively prepared, andthe crystals obtained are free from highly toxic hexane as a residualsolvent. Accordingly, these crystals can be suitably used as activeingredients of pharmaceutical products. Further, the crystals obtainedby the method of the present invention are characterized to have smallfluctuation in average grain size, and enable preparation of tabletswith a uniform content by a compression process.

What is claimed is:
 1. A method for preparing a crystal of4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid having a single endothermic peak approximately at 233° C. indifferential scanning calorimetry, which comprises the step ofrecrystallizing a crystal of4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid from a mixture of water and ethanol.
 2. A method for preparing acrystal of4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid having a single endothermic peak approximately at 233° C. indifferential scanning calorimetry, which comprises the step of heating acrystal of4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid having endothermic peaks approximately at 193° C. and 233° C. indifferential scanning calorimetry.
 3. A crystal of4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid having a single endothermic peak approximately at 233° C. indifferential scanning calorimetry, which does not contain hexane and/orethyl acetate as a residual solvent.
 4. A crystal of4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid having a single endothermic peak approximately at 233° C. indifferential scanning calorimetry, which contains residual ethanol of2,000 ppm or less after the crystal is dried at 110° C. to 120° C. underreduced pressure.
 5. A crystal of4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid having endothermic peaks approximately at 193° C. and 233° C. indifferential scanning calorimetry.